Chapter 27 Tumors of the conjunctiva
The conjunctiva is a translucent, vascularized mucous membrane that can be divided into three regions: the bulbar conjunctiva, including the corneo-conjunctival limbus, which covers the sclera in the anterior part of the eyeball; the superior, inferior, and lateral conjunctival fornices; and the palpebral conjunctiva, including the mucocutaneous transitional zone in the lid margin, which covers the posterior surface of the eyelids (Fig. 27.1).1 The conjunctiva is movable over the globe and in the fornix, where it is loosely adherent to the sclera, but fixed to the posterior surface of the eyelids, where it is markedly adherent to the tarsal plate.
Fig. 27.1 Normal eye structure: (A) schematic sagital cross-section of an eye showing the bulbar conjunctiva in light blue, the forniceal conjunctiva in green, and the tarsal conjunctiva in dark blue; (B) a sagitally cut exenteration specimen with the same colors as in (A) to mark the different parts of the inferior conjunctiva.
Although the conjunctiva is a very thin tissue, its histological constituents can give rise to many types of tumors. It is composed of epithelium and subepithelial stroma (the substantia propria). The epithelium near the limbus is continuous with the corneal epithelium, and the epithelium in the mucocutaneous epithelial zone is continuous with the eyelid epidermis; these two sites are probably the location of conjunctival stem cells.2 The epithelial cells are stratified in a columnar manner in the fornix but tend to be cuboidal in the bulbar and tarsal conjunctiva. Goblet cells are present in the middle and superficial layers of the epithelium and are most numerous in the lower forniceal portion of the conjunctiva. They are absent in the normal limbal conjunctiva. Melanocytes are scattered throughout the basal layer of the epithelium.
Conjunctival stroma is composed of fibrovascular connective tissue which is thicker in the fornix and thinner over the globe and posterior surface of the eyelids. The stroma contains collagen and elastic tissue; arteries, veins, and lymphatic vessels; nerves; and the accessory lacrimal glands of Krause and Wolfring. Similar to other mucous membranes, the conjunctiva contains associated lymphoid tissue. Numerous lymphocytes, plasma cells, mast cells, and neutrophils are normally present in conjunctival stroma. Lymphocytes may aggregate into nodules but not as true lymphoid follicles.
On the medial side of the globe, the plica semilunaris and caruncle replace the fornix. The plica semilunaris is a vertical fold of conjunctiva that lies lateral to the caruncle. It is composed of 8–10 layers of epithelial cells containing many goblet cells. The loose, highly vascular stroma can have some nonstriated muscle fibers supplied with sympathetic nerves; the stroma may also contain fatty tissue. The caruncle, which contains conjunctival and cutaneous structures as well as hair, sebaceous glands, sweat glands, and accessory lacrimal glands, is a fleshy prominence located in the medial canthus. The caruncle has an abundant blood and nerve supply and is covered with nonkeratinized, stratified squamous epithelium containing many goblet cells. Tumors of the caruncle are of mucosal or cutaneous origin.
Benign and malignant tumors arise from epithelial and stromal structures of the conjunctiva. Parts of the bulbar conjunctiva in the palpebral fissure are exposed to sunlight, which may be a factor in the pathogenesis of some conjunctival tumors. The entire conjunctiva is exposed; therefore, various external chemical, physical, and biological agents may play a role in the development of conjunctival tumors. Neoplasms originating in the eyeball, eyelid or orbit, as well as metastases from distant tumors, may invade the conjunctiva.
Because the conjunctiva is readily visible, tumors on the ocular surface are usually recognized and diagnosed at an early stage. External ocular examination and detailed evaluation with a slit lamp are vital to correctly diagnosing conjunctival tumors. Because many of these lesions have characteristic clinical features, an experienced ophthalmologist can often make an accurate diagnosis by clinical examination alone.
Since evaluating conjunctival lesions under the diffuse lighting of an operating microscope can be difficult, the extent of conjunctival and corneal involvement should be accurately documented by slit-lamp examination prior to treatment. Fluorescein or rose Bengal stains can be used to delineate abnormal epithelium and tumor margins, especially when lesions are diffuse. Conjunctival lesions should be photographed externally or via a slit lamp to accurately document the tumors and their margins.
The bulbar conjunctiva, palpebral conjunctiva, and upper and lower fornices must be evaluated for tumor involvement. Abnormal conjunctiva should be gently pushed with a cotton-tipped applicator to evaluate whether the lesion moves freely, indicating sclera sparing. Conjunctival lesions that adhere to the sclera may indicate scarring or malignancy. When the tumor is thick or adheres to the surrounding tissues, high-frequency ultrasonography can be used to determine the tumor’s depth and extension into the sclera, cornea or intraocular structures.
The entire eyeball and eyelids should be examined for possible tumor involvement. If malignancy is suspected, the preauricular and submandibular areas must be palpated for enlarged lymph nodes to check for regional metastases.
The definitive diagnosis of conjunctival or corneal tumors requires histological examination. However, asymptomatic tumors that appear benign are often managed with periodic observation, and biopsies are taken only if there is evidence of growth or malignant change. When a small tumor requires a biopsy, it is often more efficient to simply remove the lesion completely. For large conjunctival lesions, completely removing the tumor can severely compromise the ocular surface, or it may be impossible to totally excise the lesion; in such cases, an incisional biopsy is warranted. Incisional biopsy is also appropriate if the tumor is to be treated with radiotherapy, chemotherapy or local means such as cryotherapy or topical chemotherapy. Although exfoliative cytology has been used to evaluate conjunctival and corneal tumors, the method provides information only on the superficial layers of the lesion and not the invasiveness of the tumor, which may influence management.
The classification of conjunctival tumors depends on the tissue or cell of origin, the differentiation of the tumor, and the tumor’s benign or malignant status. Some tumors have subtypes that, despite having identical histogeneses, present or behave differently because of special histological structures, features or locations.
Most conjunctival tumors are epithelial or melanocytic in origin. Other conjunctival tumors arise primarily from the vascular, fibrous, neural, histiocytic, myogenic, myxoid, lipomatous or lymphoid tissues in the conjunctival stroma. There are five unique groups of conjunctival tumors: hamartomas, choristomas, caruncular tumors, and metastatic and secondary tumors.
In this chapter, the classification of conjunctival and corneal tumors is based on the second edition of the World Health Organization International Histological Classification of Tumors.3 Other major texts have also been consulted.4–6 The tumors discussed in this chapter are listed in Box 27.1.
In the clinical differential diagnosis of conjunctival tumors, the gross characteristics of the lesion must be considered in addition to clinicopathological correlation. The more important characteristics to consider are:
Although most conjunctival tumors are benign, malignant variants also occur. Conjunctival tumors are usually classified as being melanocytic or nonmelanocytic on the basis of the clinical presence or absence of brown–black pigmentation and histological evidence of melanocytes; however, nonmelanocytic tumors can also be pigmented. Melanocytic lesions include nevi, melanoses, and melanomas. While melanoses are superficial–epithelial, nevi and melanoma can also involve the stroma. In bulbar conjunctival melanosis, the lesions are movable with the conjunctiva; in melanoma, the lesions are usually fixed.
Most nonmelanocytic tumors are epithelial and are located on the surface of the conjunctiva. Epithelial tumors generally have irregular, granular or papillary surfaces and may be leukoplakic (i.e., covered with keratin) or gelatinous in appearance. Epithelial tumors can be superficial and thin, or thick and fleshy.
Stromal tumors, including metastases in the stroma, generally have smooth surfaces. Tumor color can be helpful in diagnosing conjunctival tumors. Vascular tumors are red, pink, or sometimes blue. Fibrous tumors are usually white but may also be pink. Neural, histiocytic, and lipomatous tumors are yellow, and lymphoid tumors and leukemic infiltrates are a shade of pink similar to the color of smoked salmon (hence the term ‘salmon patch’).
Congenital epibulbar tumors diagnosed in infancy and childhood are usually hamartomas or choristomas. Caruncular lesions present a special challenge in the differential diagnosis of conjunctival and cutaneous tumors. When tumors spread from surrounding structures into the conjunctiva, the primary tumor is usually known except in many cases of pagetoid spread of sebaceous gland carcinoma of the eyelid, which may originate in the conjunctiva itself.
The World Health Organization’s histological classification of conjunctival tumors includes tumor-simulating lesions such as pinguecula, pterygium, and keloid. These common conjunctival lesions can be mistaken for tumors if they are covered by keratin plaque or have a gelatinous appearance.
Pinguecula is a localized yellow–white elevated area, most commonly found in the nasal conjunctiva adjacent to the limbus, and which develops as a result of actinic (basophilic) elastotic degeneration of the substantia propria. Pterygium is a localized yellow–white elevated area found in the nasal conjunctiva that extends onto the cornea and is composed of actinic (basophilic) elastotic degeneration of the conjunctival substantia propria with dissolution of Bowman’s layer.
Conditions that may simulate pigmented conjunctival tumors include drug and metal deposits, mascara, foreign bodies, postinflammatory melanoses, and flat pigmentary patches from systemic conditions such as Addison’s disease.7 Inflammatory and infectious lesions such as lepromatous leprosy and sarcoidal nodules and, more commonly, allergic and other granulomatous nodules should be included in the differential diagnosis of conjunctival tumors.
Abnormal cellular proliferation and differentiation confined to the conjunctival epithelium may cause thickening, papillary or nodular focal elevation of the conjunctiva, or plaquelike opacification (leukoplakia). Such lesions rarely become malignant.
It presents as sessile or pedunculated pink or red fleshy fronds of tissue or finger-like projections with irregular surfaces that sometimes appear cauliflower-like (Fig. 27.2). It is often asymptomatic, without an associated inflammatory reaction. However, large pedunculated lesions are usually symptomatic and may cause foreign body sensation, mucous secretion, hemorrhagic tears, incomplete eyelid closure or poor cosmetic appearance. Although usually solitary, it can be bilateral or multiple and may become confluent.
Conjunctival squamous papilloma often occurs in the inferior fornix or bulbar conjunctiva but may present in any part of the conjunctiva, including the palpebral conjunctiva, lid margin, caruncle, and plica semilunaris. According to one study, papillomas are located medially and inferiorly, which is explained by the direction of the flow of tears.4 Conjunctival papillomas tend to recur frequently, particularly if there are multiple lesions or the conjunctiva is infected with human papillomavirus (HPV).
In adults, conjunctival squamous papilloma is usually single and unilateral, commonly arising close to the limbus or bulbar conjunctiva. Conjunctival squamous papilloma is generally broad-based and flat and may become large, covering much of the conjunctiva; occasionally, a lesion covers the cornea and interferes with vision. Differentiating such lesions clinically from squamous cell carcinoma can be difficult.
In children, squamous papillomas have been found to be associated with HPV (mostly types 6 and 11) infection of the conjunctiva. Histologically, squamous papilloma in children is composed of epithelial projections covered with nonkeratinized, acanthotic stratified squamous epithelium in which goblet cells are sometimes present. The fibrovascular cores of these lesions typically contain acute and chronic inflammatory cells (Fig. 27.3). The basement membrane is always intact. HPV may be identified using a variety of immunohistochemical and molecular techniques.5,6
In adults, conjunctival squamous papillomas usually have broader bases and may have acanthotic epithelium showing varying, though generally mild, degrees of cytological atypia (dysplasia). Conjunctival squamous papillomas are usually nonkeratinized; however, moderate keratinization sometimes occurs. The basement membrane is typically intact.
Inverted papillomas are exceedingly rare, solid or cystic solitary nodules that occur in the limbus, plica semilunaris, and tarsal conjunctiva. They are so named for their propensity to invaginate inward into the underlying conjunctival substantia propria instead of growing in an exophytic manner similar to other conjunctival papillomas. Some of these lesions may show a mixed inverted–exophytic papilloma.1
Histologically, lobules of proliferating nonkeratinized, noninflamed epithelial cells invaginate underlying connective tissue. Mucus-producing goblet cells are scattered throughout the lesion. Mucoid material, when present, is found in the wall of the cystic structure.
Unlike inverted papillomas in the nose, paranasal sinuses or lacrimal sac, conjunctival inverted papillomas do not generally exhibit locally aggressive behavior, involve extensive segments of the conjunctival epithelium or display diffuse spread or multicentricity. Therefore, conjunctival inverted papilloma should be clearly distinguished from inverted squamous papillomas of the nasal cavity and sinuses.2 However, there is a single case report documenting malignant change within an apparent inverted papilloma.3 Complete removal of this lesion is therefore recommended.
Reactive epithelial hyperplasia (pseudoepitheliomatous hyperplasia, pseudocarcinomatous hyperplasia) occurs secondary to irritation caused by concurrent or pre-existing stromal inflammation.1–3 It presents as an elevated, leukoplakic pink lesion that usually occurs in the limbic area. Histologically, it shows acanthosis, hyperkeratosis or parakeratosis and subepithelial inflammation. Mitotic figures may be present, but cytological atypia is generally absent. Clinically and histologically, reactive epithelial hyperplasia may be difficult to differentiate from conjunctival squamous cell carcinoma. An infiltrative growth pattern, marked cytological atypia, and excessive mitotic activity (including atypical forms) obviously favors the latter diagnosis.
Keratoacanthoma, a very rare variant of conjunctival reactive epithelial hyperplasia, is a rapidly growing benign, solitary, gelatinous or leukoplakic nodule on the bulbar conjunctiva that does not spontaneously regress and is surrounded by dilated blood vessels.1–3 In some cases, it shows an umbilicated center (Fig 27.4). It presents in the middle aged and has a predilection for males.4 In some cases there is a prior history of a foreign body in the eye.
Histologically, the lesion shows marked invasive acanthotic epithelium with keratin-filled pseudocysts, hyperkeratosis, and parakeratosis. Cytological atypia is usually minimal; in cases of keratoacanthoma with a marked degree of atypia, distinguishing the lesion from well-differentiated squamous cell carcinoma (SCC) may be difficult. An infiltrative growth pattern and excessive mitotic activity (including atypical forms) obviously favors the latter diagnosis.
Hereditary benign intraepithelial dyskeratosis (HBID) is a nonmalignant, autosomal dominant disorder, with a high degree of penetrance. It is char-acterized by bilateral elevated fleshy plaques surrounded by dilated conjunctival vessels on the nasal or temporal perilimbic bulbar conjunctiva and causes the eye to appear red (Fig. 27.5).1,2 In mild cases, HBID patients are asymptomatic; however, in severe cases, most of the bulbar conjunctiva and cornea is involved, causing corneal opacification and vascularization, leading to blindness. Patients may complain of a foreign body sensation, photophobia, and tearing. Similar lesions sometimes occur in the buccal mucosa.3 HBID occurs primarily in descendants of an inbred, isolated population of European, African-American, and Native American (Haliwa Indian) origin in Eastern North Carolina. HBID has been subsequently detected in other parts of the United States. Using genetic linkage analysis, the HBID gene has been localized to chromosome 4 (4q35).4
Histologically, HBID is characterized by acanthosis, prominent dyskeratosis in the surface and deep epithelium, and severe chronic inflammation in the stroma (Fig. 27.6). The basement membrane is intact.
Fig. 27.6 Hereditary benign intraepithelial dyskeratosis: histology of the lesion shown in Figure 27.5 displaying acanthosis, hyperkeratosis, dyskeratosis, and marked chronic inflammation in the stroma, beneath the intact basement membrane.
By courtesy of G. Klintworth, MD, Duke University Medical Center, Durham, North Carolina, USA.
Dacryoadenoma, an exceedingly rare conjunctival tumor that occurs in children and young adults, is a translucent pink lesion that occurs in the bulbar, forniceal or palpebral conjunctiva.1 Whether the lesion is congenital or acquired remains unknown.
Oncocytoma, also known as oxyphilic cell adenoma, is a rather common lesion of the lacrimal gland that often arises as a slow-growing, benign yellow–tan or reddish lesion in the caruncle or adjacent plica semilunaris and canthal conjunctiva. It presents in older individuals, usually women.1–3
Histologically, large cells with eosinophilic granular cytoplasm are arranged in nests, cords or sheets that may form glandular or ductal structures (Fig. 27.7). Ultrastructurally, the cytoplasm is laden with mitochondria. Oncocytoma rarely undergoes carcinomatous transformation.
Conjunctival epithelial cysts are common and may be congenital or acquired. Acquired cysts, which are more common than congenital variants, are mostly epithelial inclusion cysts that occur spontaneously or after surgical or nonsurgical trauma (Fig. 27.8).1,2 Ductal cysts, which usually arise from the accessory lacrimal gland, are also common.
By courtesy of Y. Deckel, MD, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Clinically, these cysts are smooth, translucent lesions which contain clear fluid; however, the fluid may be turbid or contain epithelial debris layered like pseudohypopyon in the lumen. In patients with dark complexions, they may be pigmented. The cysts can be stable and asymptomatic or enlarge and become symptomatic, necessitating excision. In most cases, however, they eventually disappear.
Histologically, epithelial inclusion cysts are lined with conjunctival epithelium. Goblet cells may be present.3 The lumen can be clear, or it can contain mucinous material, epithelial debris or keratin. Ductal cysts are lined with two layers of epithelium and may contain periodic acid-Schiff-positive material (Fig. 27.9).
Actinic keratosis, a precancerous lesion also known as conjunctival dysplasia, actinic keratosis variety, is a rarely diagnosed focal leukoplakic lesion occurring at the intrapalpebral limbus, usually over a chronically inflamed pinguecula or pterygium.1–3
Ocular surface squamous neoplasia (OSSN) represent precancerous and cancerous epithelial lesions of the conjunctiva and cornea.1,2 The term includes dysplasia, carcinoma in situ, and invasive squamous cell carcinoma. Previously, intraepithelial OSSN was known as ‘intraepithelial epithelioma’, ‘Bowen’s disease of the conjunctiva’ or ‘bowenoid epithelioma’ because of its histological similarities to Bowen’s disease of the skin. Currently, these lesions are also known as conjunctival intraepithelial neoplasia (CIN).3
Ocular surface squamous neoplasia is found in all races. It is uncommon in the Northern hemisphere and is much more often seen in countries closer to the equator and in areas where people are exposed to sunlight more frequently. The incidence of OSSN in the United States is approximately 0.03 per 105 of the population.4 In Uganda, the incidence of OSSN is about 0.13 per 105, and in Australia, the incidence rate is around 1.9 per 105.1 Although OSSN occurs predominantly in adults, there are a small number of reports of childhood lesions.5 According to some studies, intraepithelial squamous neoplasia presents in patients who are 5–9 years younger than patients with invasive tumors, suggesting that precancerous CIN may become invasive SCC.6 OSSN is more common in men than women, which can be explained at least in part by the greater exposure to sunlight men receive from working outdoors.4
Clinically, conjunctival epithelial dysplasia, carcinoma in situ, and invasive squamous carcinoma may be difficult to distinguish from one another. Although these lesions commonly arise within the interpalpebral fissure, mostly at the limbus, they can be found in any part of the conjunctiva and cornea (Figs 27.11–27.13). They present clinically in a variety of ways including gelatinous lesions with superficial vessels; papillary structures or as leukoplakia with a white keratin plaque covering the lesion.3 OSSN may also appear in a nodular form, especially when it represents an invasive squamous carcinoma, or as a diffuse lesion that may be mistaken for chronic conjunctivitis.
Fig. 27.11 Ocular surface squamous neoplasia (OSSN): there is an elevated erythematous bulbar conjunctival lesion adjacent to the temporal (9 o’clock) limbus of a left eye. Note the dilated feeding vessels.
Fig. 27.12 Ocular surface squamous neoplasia (OSSN): there is a flat erythematous lesion in the nasal (9 o’clock) conjunctiva of the right eye that extends onto the entire circumference of the cornea where it causes an opaque ground-glass appearance.
Fig 27.13 Ocular surface squamous neoplasia (OSSN): (A) the irregular corneal epithelium that covers the superior half of the cornea has resulted in a ground-glass appearance; (B) it can also be visualized by irregular fluorescein staining.
The clinical features of OSSN can lead to a correct diagnosis. However, because conjunctival tumors may show certain similarities, distinguishing between intraepithelial and invasive squamous neoplasia and other lesions such as pinguecula and pterygium may be difficult, especially in cases with concurrent leukoplakia or squamous papilloma. Use of fluorescein or rose Bengal staining can facilitate diagnosis by emphasizing the papillary or granular surface of part of the OSSN and help in delineating the lesion’s borders (see Fig. 27.13b). Recently, high-frequency ultrasonography has been used in the diagnosis of OSSN, particularly in estimating the depth of tumor invasion.7 However, the definitive diagnosis must be histological.
The main lesions included in the clinical differential diagnosis are pinguecula, pterygium, and squamous papilloma.3 Although OSSN usually appears as a nonpigmented lesion, pigmented conjunctival squamous cell carcinoma can be encountered. Lesions may be accompanied by redness and irritation. Visual acuity is usually not reduced unless the center of the cornea is affected. OSSN may grow within weeks to years; in most cases, however, the history is of several months.
OSSN is a low-grade malignancy.3 CIN, including dysplasia and carcinoma in situ, are precancerous lesions that rarely progress to invasive SCC. However, CIN lesions commonly recur after surgical excision, depending on the involvement of the surgical margins.3 Erie and coworkers reported that 24% of patients had a recurrence after excision of CIN and 41% of patients had a recurrence after excision of squamous cell carcinoma.6 Lee and coworkers found recurrence rates of 17% in patients with conjunctival dysplasia, 40% of patients with carcinoma in situ, and 30% in patients with SCC.1 In the same series, it was reported that 31% of patients had a second recurrence, and 8% of patients had more than two recurrences. Although most tumor recurrences develop within 2 years, later recurrences may also occur. New treatment methods including photodynamic therapy, mitomycin C, and interferon alpha-2b have reduced the recurrence rate significantly.
Although rare, intraocular invasion associated with OSSN may occur, typically in older patients who have squamous carcinoma near the corneoscleral limbus with one or more recurrences after surgical excision.8 Histopathological examination may show invasive tumor through the limbus and involving Schlemm’s canal, trabecular meshwork, anterior chamber, iris, ciliary body, suprachoroidal space, and choroid, sometimes even behind the equator. In very advanced cases, squamous carcinoma may involve the entire orbital content (Fig. 27.14).
Metastatic conjunctival squamous carcinoma is extremely rare but the parotid gland, lungs, bones, and preauricular, submandibular, and cervical lymph nodes may be involved.6,9 The main cause of metastasis is delay in diagnosis and treatment. Because regional lymph node involvement precedes the development of distant metastases, these lymph nodes should be examined on a regular basis to enable lymph node and radical neck dissection in cases with nodal involvement. Local invasion and distant metastases rarely cause death in conjunctival SCC patients.9
Exposure to solar ultraviolet radiation is a major etiologic factor in the development of OSSN.3,6 The rarity of OSSN in Europe and North America and its high incidence in sub-Saharan African countries and Australia, where people are more exposed to sunlight, suggests that ultraviolet radiation exposure plays an important role in the development of OSSN.1 Lee and coworkers reported a significant relationship between lifetime exposure to solar ultraviolet light and the development of OSSN.1 Similarly, Newton and coworkers found that the incidence of squamous carcinoma of the eye increases by 29% per unit increase in exposure to ambient solar ultraviolet radiation, equivalent to a 49% increase in incidence with each 10° decline in latitude.10 A history of actinic skin lesions such as solar keratoses and squamous carcinoma was also found to be strongly associated with the development of OSSN. Ultraviolet B rays damage DNA in human epithelial cells. Failure in DNA repair, as occurs in xeroderma pigmentosum, leads to somatic mutation and the development of cancerous cells, including OSSN.
In recent years, HPV, mainly type 16, has been demonstrated in OSSN tissue.11 HPV DNA was found in OSSN tissue using amplification with PCR and DNA sequencing, in ocular surface swabs of OSSN patients, and in studies of formalin-fixed, paraffin-embedded tissue using immunohistochemistry. However, HPV may also be detected in uninvolved eyes with apparently healthy conjunctiva and in cases of persistent infection many years after successful eradication of OSSN. In a study in which antibodies against HPV were examined in OSSN, no statistically significant association between anti-HPV antibody status and the risk of conjunctival neoplasia was found, indicating that HPV alone may be incapable of causing OSSN.12
The incidence of OSSN has increased significantly since the development of the HIV/AIDS epidemic, especially in sub-Saharan African countries.13 In Rwanda, Uganda, Congo-Kinshasa, and Zimbabwe, HIV infection is strongly associated with an increase in incidence of OSSN. In these countries, OSSN tends to occur at a younger age than previously reported and appears to grow faster, indicating high aggressiveness. Although HIV infection alone seems to be a risk factor for OSSN, the interaction of HIV, ultraviolet light, and HPV appears to accelerate the development of OSSN in this part of the world.
Given the high incidence of OSSN in the limbic area, where the stem cells for the corneal and conjunctival epithelium are located, Lee and coworkers posited the limbic transition zone/stem cell theory for the development of OSSN.1 Based on Tseng’s concept of the long-living and high proliferation rate of stem cells in the limbic area, Lee and coworkers postulated that alterations in the limbic area could cause abnormal maturation of the conjunctival and corneal epithelium, resulting in OSSN.
Preoperative cytological diagnosis may help prevent removal of unnecessarily large pieces of normal conjunctiva in cases of benign lesions and avoid partial excision in cases of malignant lesions, thus sparing normal conjunctiva. One method used to diagnose OSSN preoperatively is exfoliative cytology, in which a platinum spatula, brush, or cotton-wool tip is used to obtain cells from the conjunctival surface and Papanicolaou and Giemsa stains are used to examine the cells.14 Exfoliative cytology can be used to obtain prospective cytological information about the lesion, mainly to detect malignancy; furthermore, it can be used to sample multiple sites easily and provides a convenient method of follow-up evaluation. However, because a very superficial sample – sometimes consisting of keratinized cells only – is obtained, exfoliative cytology does not enable evaluation of the structure of the lesion or the degree of tumor invasion, factors that are crucial in determining management.
Another method of obtaining cells from the surface of conjunctival lesions is impression cytology, in which several types of filter paper, such as cellulose acetate filter paper, Millipore filter paper or Biopore membrane device, are gently placed on the ocular surface to sample the most superficial cells and then fixed and stained with Papanicolaou stain.15 Impression cytology has the same advantages and disadvantages as exfoliation cytology.
Fig. 27.15 Ocular surface squamous neoplasia (OSSN) with severe dysplasia: histology of a piece of conjunctival tissue with acanthosis and severe dysplasia of the epithelium. The changes, however, do not affect the full thickness of the epithelium.
Three variants of invasive, sometimes aggressive, conjunctival squamous carcinomas have been described.2 Spindled cell squamous carcinoma exhibits spindled cells that may be difficult to distinguish from fibroblasts. Mucoepidermoid carcinoma has mucous-secreting cells that are stained positively with special stains for mucopolysaccharides. Adenoid squamous carcinoma shows extracellular hyaluronic acid but no intracellular mucin. Because of the potential aggressiveness of these variants, which may invade the eyeball or orbital tissue or even metastasize, it is important that they are distinguished from the less aggressive conventional tumor.
OSSN arising in the corneal epithelium is rare.6,16 Some authors postulate that the corneal epithelium has the potential to undergo dysplastic and malignant change,17 while other authors think that corneal OSSN originates in the limbus. Histologically, corneal lesions are similar to those that occur in the limbus and conjunctiva. The Bowman’s layer is usually intact. Corneal CIN may rarely recur due to inadequate scraping.9,10
Conjunctival nevi are the most common conjunctival lesions. The various types of nevi in addition to other benign melanocytic lesions of the conjunctiva, episclera, and sclera, including complexion-associated melanosis, ocular melanocytosis, and primary acquired melanosis (PAM) without atypia, are discussed in this section. Many other pigmented conjunctival lesions that are not of melanocytic origin should always be included in the differential diagnosis of melanocytic conjunctival lesions.
Circumscribed nevi are the most common melanocytic tumors of the conjunctiva.1,2 Although they can appear in all races, they are most commonly seen in Caucasians. Nevi that appear at birth or within the first 6 months of life are generally considered congenital, while those that appear more than 6 months after birth are regarded as acquired. Most acquired conjunctival nevi appear during the first two decades of life. Melanocytic conjunctival lesions that appear after the first two decades of life may represent PAM or melanoma.
Conjunctival nevi are typically located in the interpalpebral bulbar conjunctiva, commonly near the limbus, and rarely involve the cornea.2 The presence of melanocytic tumors in locations other than bulbar conjunctiva, plica semilunaris or caruncle is rare and should raise suspicion for PAM or melanoma.
Clinically, conjunctival nevi are discrete, variably pigmented, slightly elevated sessile lesions that typically contain cystic structures which can be seen with the naked eye or on slit-lamp biomicroscopy (Fig. 27.20). Conjunctival nevi may vary in size from tiny lesions to larger ones that occupy much of the bulbar conjunctiva. Nevi can become darker or lighter as a patient ages. They sometimes become more pink and congested because of inflammatory changes. However, conjunctival nevi usually do not change in size or color after adolescence, and such changes during adulthood should raise suspicion for malignant transformation. Conjunctival nevi can be clinically amelanotic. The presence of cystic structures may help to differentiate such conjunctival nevi from other amelanotic conjunctival lesions.
By courtesy of I. Anteby, MD, Hadassah-Hebrew University Medical Center, Jerusalem, Israel